Chitosan Loaded Mucoadhesive Microspheres of Gliclazide - Journal
Chitosan Loaded Mucoadhesive Microspheres of Gliclazide - Journal
Chitosan Loaded Mucoadhesive Microspheres of Gliclazide - Journal
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ABSTRACT<br />
RGUHS <strong>Journal</strong> <strong>of</strong> Pharmaceutical Sciences<br />
Effect <strong>of</strong> Different Acids on the Formation <strong>of</strong> E and Z Isomers <strong>of</strong> Dothiepin<br />
1 2 1 3<br />
Gopal Krishna Rao* , Ramesha A.R , Amit Kumar Jain and Sanjay Pai P.N<br />
1<br />
Department <strong>of</strong> Pharmaceutical Chemistry, Al-Ameen College <strong>of</strong> Pharmacy, Bangalore, Karnataka, India<br />
3 Dept. <strong>of</strong> Quality Assurance, Al-Ameen College <strong>of</strong> Pharmacy, Bangalore, Karnataka, India<br />
2 R.L.Fine Chemicals, Yelahanka, Bangalore, Karnataka, India<br />
Dothiepin is an antidepressant drug useful in the treatment <strong>of</strong> mild to moderate endogenous depression. The synthesis <strong>of</strong> dothiepin<br />
involves dehydration <strong>of</strong> alcohol using acid catalysis leading to the formation <strong>of</strong> E- and Z- isomers. So herein, we report the use and effect<br />
<strong>of</strong> various acid catalysts on the formation E- and Z- isomers. Characterization <strong>of</strong> both the isomers was achieved by using HPLC and<br />
NMR. Both NMR and HPLC analysis showed the formation <strong>of</strong> E-isomer as the major component.<br />
Keywords: Dothiepin, E and Z isomer, NMR and HPLC<br />
INTRODUCTION<br />
Many important and widely used drugs are marketed as<br />
mixture <strong>of</strong> optical isomers that <strong>of</strong>ten differ in<br />
pharmacological, toxicological and pharmacokinetic<br />
1<br />
properties . Qualitatively and quantitatively enantiomers may<br />
have similar or different pharmacological effects. This may be<br />
related to stereo selective pharmacokinetics or<br />
pharmacodynamics. The terms 'eutomer' for the more potent<br />
isomer and 'distomer' for the less potent one have been <strong>of</strong>ten<br />
used. No generalizations can be made concerning<br />
enantiomers since they exhibit varied effects, e.g.,<br />
cyclophosphamide and flecainide for equipotent<br />
enantiomers; one enantiomer with all or most <strong>of</strong> the activity<br />
as exhibited by NSAID's and β-blockers; both enantiomers<br />
active with similar therapeutic and toxic effects but different<br />
magnitude as shown by warfarin and both enantiomers active<br />
but with quantitatively different therapeutic and toxic effects<br />
2<br />
as evidenced by verapamil . Hence efforts in formation <strong>of</strong> one<br />
<strong>of</strong> the isomers <strong>of</strong> high pharmacological importance during<br />
the synthesis itself can be <strong>of</strong> immense value.<br />
Dothiepin, chemically is N,N-dimethyl-3-(dibenz[b,e]<br />
thiepin-11(6H)-ylidene) propylamine. It also differs in<br />
structure from amitriptyline by the presence <strong>of</strong> sulphur atom<br />
in the central ring, which leads to the formation <strong>of</strong> E and Z<br />
isomer. Of the two isomers, E isomer is predominant in its<br />
3<br />
composition . Dothiepin, a tricyclic antidepressant possesses<br />
marked anticholinergic and sedative properties and is also<br />
known to prevent reuptake <strong>of</strong> noradrenaline and serotonin at<br />
nerve terminals. The tricyclic antidepressants are particularly<br />
4<br />
useful in the treatment <strong>of</strong> endogenous depression .<br />
RGUHS <strong>Journal</strong> <strong>of</strong> Pharmaceutical Sciences<br />
Received: 6/4/2011, Modified: 12/5/2011, Accepted: 21/5/2011<br />
172<br />
Original Research Article<br />
In continuation <strong>of</strong> our efforts in understanding the catalytic<br />
effects <strong>of</strong> various acids on the formation <strong>of</strong> E and Z isomers <strong>of</strong><br />
5<br />
doxepin and encouraging results obtained therein, we hereby<br />
report the effect <strong>of</strong> various acids on the formation <strong>of</strong> E and Z<br />
isomers <strong>of</strong> Dothiepin.<br />
Dothiepin was synthesized using different acid catalysts on<br />
(11RS)-11-[3-(Dimethyl amino) propyl]-6,11dihydrodibenzo[b,e]<br />
thiepin-11-ol (Compound A). Using<br />
NMR technique we were able to identify the isomers and<br />
confirm the E- and Z- isomer formation in the experiments<br />
involving use <strong>of</strong> various acids. This study was confirmed by<br />
HPLC to know the percentage <strong>of</strong> both the isomers in<br />
6<br />
dothiepin .<br />
MATERIAL AND METHOD<br />
The chemicals and reagents used in the present project were<br />
<strong>of</strong> AR grade and LR grade and were purchased from<br />
Lancaster, Sigma, NR Chem etc. Melting points <strong>of</strong> the<br />
synthesized compounds were determined in open capillary<br />
1<br />
tubes and are uncorrected. H NMR (400 MHz) spectra were<br />
recorded in deuterated chlor<strong>of</strong>orm in Amx-200 liquid state<br />
NMR spectrometer (Astra Zeneca, Bangalore) using TMS as<br />
internal standard. HPLC chromatograms were recorded on<br />
Shimadzu SPD10 A UV-visible detector, Ray Chemicals Pvt<br />
Ltd,Yelahanka,Bangalore.<br />
STEP-1: General procedure for preparation E- & Z-<br />
isomers <strong>of</strong> N,N-dimethyl-3- (dibenzo[b,e]thiepin-<br />
11(6H)ylidene) propylamine (1a-g)<br />
( 1 1 R S ) - 1 1 - [ 3 - ( D i m e t h y l a m i n o ) p r o p y l ] - 6 , 1 1 -<br />
9<br />
dihydrodibenzo[b,e]thiepin-11-ol [Compound A] (10 g,<br />
0.0311 mol) was taken in a 500 ml round bottom flask, to<br />
which acid (0.0377 mol) and toluene (100 ml) was added with<br />
stirring at 110 °C. The reaction mixture was stirred for a<br />
RJPS, Jul - Sep, 2011/ Vol 1/ Issue 2